Phenyl propenone compounds

ABSTRACT

The invention relates to a process for the enantioselective preparation of tolterodine and analogues and salts thereof comprises the steps of: 
     a) enantioselectively reducing the carbonyl function in a compound of formula (II):                    
      wherein R 1 , R 2  and R 3  independently of each other are hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):                    
      wherein R 1 , R 2  and R 3  are as defined above; 
     b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb):                    
      wherein R 1 , R 2  and R 3  are as defined above; 
     c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form a corresponding enantiomerically enriched compound of the general formula (Va) or (Vb):                    
     wherein R 1 , R 2  and R 3  are as defined above; 
     d) converting the compound of formula (Va) or (Vb) to form the corresponding enantiometrically enriched compound of tolterodine or analogue, and 
     e) optionally converting a compound obtained in base form to a salt thereof, or converting a salt form to the free base. 
     The invention also relates to novel starting materials and intermediates used in the process.

RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.09/919,401 filed Jul. 31, 2001, now U.S. Pat. No. 6,566,537, which inturn was a divisional of U.S. application Ser. No. 09/748,042 filed Dec.22, 2000, now U.S. Pat. No. 6,310,248, which in turn claims priorityunder 35 U.S.C. §119 of U.S. Provisional Application Ser. No. 60/177,439filed Jan. 21, 2000.

FIELD OF THE INVENTION

The present invention relates to a novel process of preparingtolterodine and analogues thereof, as well as to novel intermediatesprepared in the process.

BACKGROUND OF THE INVENTION

Tolterodine, i.e.(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, isuseful for treating urinary incontinence. The major, active metaboliteof tolterodine, i.e.(R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine,contributes significantly to the therapeutic effect of tolterodine.Tolterodine and analogues thereof, including the corresponding(S)-enantiomer, as well as processes for the preparation thereof aredisclosed in U.S. Pat. No. 5,382,600. The active metabolite andanalogues are disclosed in U.S. Pat. No. 5,559,269. The (S)-enantiomerand its use in the treatment of urinary and gastrointestinal disordersis further described in WO 98/03067.

One of the processes described in U.S. Pat. No. 5,382,600 comprises thesteps of preparing the lactone3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, reductivelyring-opening the lactone to prepare the corresponding alcohol, reactingthe alcohol with isopropylamine, and resolving the racemate formed toisolate tolterodine.

U.S. Pat. No. 5,922,914 discloses a modified process for preparingtolterodine by reducing the above-mentioned lactone to the correspondingalcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol, reductivelyaminating the alcohol, and resolving the racemate formed to isolatetolterodine.

While the above prior art methods thus produce a racemate which has tobe resolved to obtain the desired tolterodine enantiomer, Andersson,Pher G. et al., J. Org. Chem. 1998, 63, 8067-8070 discloses anenantioselective synthesis of tolterodine which obviates the need of theenantiomer separation step. This method comprises a copper bromidecatalyzed asymmetric addition of 2-methoxy-5-methylphenylmagnesiumbromide to a 3-phenyl-prop-2-enoyl-oxazolidinone to produce the(5S)-phenyl-3R)-2-benzyloxy-5-methylphenyl)-3-phenylpropanoyl-2-oxazolidinone,hydrolyzation of the oxazolidinone to the corresponding propanoic acid,reaction with diisopropylamine to form the amide, and reduction of theamide to tolterodine.

SUMMARY OF THE INVENTION

The present invention provides an alternate enantioselective synthesisof tolterodine which is more convenient to perform than the prior artmethod outlined above and which gives a final product of highenantiomeric purity. A key step of the present method is the preparationof the above-mentioned lactone,3,4-dihdyro-6-methyl-4-phenyl-2H-benzopyran-2-one (also referred to as6-methyl-4-phenyl-chroman-2-one), in an enantiomerically enriched formby enantioselective reactions.

Thus, in a first aspect the present invention provides a process for theenantioselective preparation of a compound of the general formula (Ia)or (Ib):

 wherein R₁, R₂ and R₃ independently of each other are hydrogen, methyl,methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, andR₄ and R₅ independently of each other are C₁₋₆-alkyl, or a salt thereof,which process comprises the steps of:

a) enantioselectively reducing the carbonyl function in a compound offormula (II):

 wherein R₁, R₂ and R₃ are as defined above, to form an enantiomericallyenriched compound of formula (IIIa) or (IIIb):

 wherein R₁, R₂ and R₃ are as defined above, or a salt thereof;

b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropicrearrangement to form a corresponding enantiomerically enriched compoundof formula (IVa) or (IVb):

 wherein R₁, R₂ and R₃ are as defined above, or a salt thereof;

c) subjecting the compound of formula (IVa) or (IVb) to aBaeyer-Villiger oxidation to form a corresponding enantiomericallyenriched compound of the general formula (Va) or (Vb):

 wherein R₁, R₂ and R₃ are as defined above or a salt thereof;

d) converting the compound of formula (Va) or (Vb) to form thecorresponding enantiometrically enriched compound of formula (Ia) or(Ib), or a salt thereof; and

e) optionally converting a compound of formula (Ia) or (Ib) in base formto a salt thereof, or converting a salt form to the free base.

In one embodiment of the first aspect of the invention, step d)comprises:

d1) reacting the compound of formula (Va) or (Vb) with an amine of thegeneral formula (VI):

 wherein R₄ and R₅ are as defined above, to form a correspondingenantiomerically enriched compound of the general formula (VIIa) or(VIIb):

 wherein R₁, R₂, R₃, R₄ and R₅ are as defined above; and

d2) reducing the carbonyl function in the compound of formula (VIIa) or(VIIb) to form the corresponding enantiomerically enriched compound offormula (Ia) or (Ib).

Optionally, steps d1) and d2) are performed simultaneously in a singlestep.

In an alternative embodiment, step d) comprises:

d1′) reducing the compound of formula (Va) or (Vb) to form acorresponding enantiomerically enriched hydroxy compound of the generalformula (VIIIa) or (VIIIb):

 wherein R₁, R₂ and R₃ are as defined in claim 1; and

d2′) reductively aminating the hydroxy compound of formula (VIIIa) or(VIIIb) with the amine of formula (VI) to form the correspondingenantiomerically enriched compound of formula (Ia) or (Ib).

In second aspect, the present invention provides a process for theenantioselective preparation of a compound of the general formula (Va)or (Vb):

 wherein R₁, R₂ and R₃ are as defined above, or a salt thereof, whichprocess comprises the steps of:

a) enantioselectively reducing the carbonyl function in a compound offormula (II):

 wherein R₁, R₂ and R₃ are as defined above, or a salt thereof, to forman enantiomerically enriched compound of formula (IIIa) or (IIIb):

 wherein R₁, R₂ are R₃ are as defined above, or a salt thereof;

b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropicrearrangement to form a corresponding enantiomerically enriched compoundof formula (IVa) or (IVb):

 wherein R₁, R₂ and R₃ are as defined above, or a salt thereof; and

c) subjecting the compound of formula (IVa) or (IVb) to aBaeyer-Villiger oxidation to form the corresponding enantiomericallyenriched compound of the general formula (Va) or (Vb), or salt thereof.

The compound of formula (II) may be prepared by subjecting a compound ofthe general formula (IX):

 wherein R₁, R₂, and R₃ are as defined in claim 1, and Hal is halogen(preferably bromine), or a salt thereof, to a reductive ring closurereaction.

The compound of formula (IX) may be prepared by reacting a compound ofthe general formula (X):

 wherein R₁ and Hal are as defined above, with a compound of the generalformula (XI):

 wherein R₂ and R₃ are as defined above.

Preferably, compounds of formula Ia or Ib are prepared in which R₁ ismethyl or hydroxymethyl in 5-position, R₂ and R₃ are hydrogen, and R₄and R₅ are both isopropyl.

In a third aspect, the present invention provides novel compounds of theabove of the formulae (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb),and (IX) as defined above and wherein R₁ is methyl or hydroxymethyl in5-position, or for (Va) and (Vb), in 6-position, and R₂ and R₃ arehydrogen and compounds of the formulae (IX) wherein R₁ is methyl orhydroxymethyl in 5-position or 4-position, R₂ and R₃ are hydrogen andhalogen is Br, I or F.

DETAILED DESCRIPTION OF THE INVENTION

A basic concept behind the present invention is the enantioselectivereduction of the compound of formula (II) to a compound of formula(IIIa) or (IIIb) in enantiomerically enriched form, which is thenrearranged to form the lactone (Va) or (Vb). The respective lactoneenantiomers may then be reacted further to tolterodine by methods knownper se in the art, e.g. as described in the above-mentioned U.S. Pat.No. 5,382,600 and U.S. Pat. No. 5,922,914.

The enantioselective reduction of the compound (II) to a compound offormula (IIIa) or (IIIb) may be performed in an organic solvent with avariety of reducing agents and reaction conditions as are known per sein the art for enantioselective reduction of carbonyl groups. Suchmethods are described in, for example, Houben-Weyl, StereoselectiveSynthesis, Ed: Günter Helmchen et al., Vol. 7, Chapter 2.3, Thime,Stuttgart-New York 1996. Preferably, the reaction is carried out at fromabout 0° C. to about room temperature. An exemplary method includes theuse of a chiral catalyst, such as (R)- or (S)-MeCBS(3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[1,2-c][1.3.2]oxazaborole)which is commercially available, a borane complex and a base. Thestereochemistry can be directed by using either the R or S enantiomer ofthe MeCBS oxazaborolidine catalyst in the asymmetric borane reduction ofthe compound (II). The reduction of a similar substrate is described in,for example, WO 97/17341. The enantioselectivity of asymmetric boranereductions is not very sensitive to stereoelectronic effects.

The sigmatropic 1,3-rearrangement (hydride shift) of the compound (IIIa)or (IIIb) to a compound of formula (IVa) or (IVb) may be carried out bytreatment with a base, such as triethylamine, and a palladium catalyst,such as Pd(dppe)Cl₂ ([1,2-bis(diphenylphosphino)ethane]palladium (ii)chloride) in an organic solvent (see e.g. the above WO 97/17341).Alternatively, the rearrangement reaction may be carried out bytreatment with DABCO (1,4-diazabicyclo[2.2.2]octane) and a base, such astriethylamine, in an organic solvent (see Example 1 below). The indanone(IVa) or (IVb) obtained is generally a highly crystalline solid whichmakes it possible to raise the enantiomeric purity, if desired, byrecrystallization from a suitable solvent (for example, an enantiomericexcess (as defined below) of 99% or more may be obtained).

The Baeyer-Villiger oxidation of compounds (IVa) and (IVb) may beperformed by a variety of oxidizing agents as is well known in the art,e.g. hydrogen peroxide or a peroxy acid, such as 3-chloro-peroxybenzoicacid, preferably in the presence of an acid catalyst, such asp-tolysulphonic acid (TsOH). The reaction is preferably carried out inan organic solvent and at e.g. from about 0° C. to about roomtemperature.

Enantiomeric purity, or enantiomeric enrichment, is usually expressed as“enantiomeric excess”, below abbreviated as “ee”, and defined as(R−S)/(R+S), where R and S are the amounts of the R- and S-enantiomers,respectively. For the purposes of the present invention, theenantiomeric purity in the enantioselective process steps is usually atleast about 50%, preferably at least about 85%.

Since tolterodine is an amine, it may form salts with both organic andinorganic acids. The pharmaceutically acceptable salts may, depending onthe pharmaceutical formulation, be preferred over the corresponding freeamines since they produce compounds which are more water soluble andmore crystalline. Exemplary pharmaceutically acceptable salts includesalts with acids such as methane sulphonic, hydrochloric, hydrobromic,sulphuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, andmaleic acids.

The invention will now be illustrated further by the followingnon-limiting Example.

In the Example:

TLC refers to thin-layer chromatography.

MeCBS refers to3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[1,2-c][1.3.2]oxazaborole.

DABCO refers to 1,4-diazabicyclo[2.2.2]octane.

ChiralCel OD-H (trademark) refers to a chiral stationary phase forliquid chromatography consisting of cellulose tris(3,5-dimethylphenylcarbamate) on a silica gel substrate (Daicel Chemical Industries, Ltd.).

mCPBA refers to 3-chloroperoxybenzoic acid.

“ee” refers to enantiomeric excess as defined above.

EXAMPLE 1 1-(2-Bromo-4-methyl-phenyl)-3-phenyl-propenone

To a solution of 2-bromo-4-methylacetophenone (7.20 g, 34.0 mmol) andbenzaldehyde (3.65 g, 34.0 mmol) in dry methanol (50 ml) was addedfreshly prepared sodium methoxide (35.7 mmol) in dry methanol (30 ml) at0° C. The resulting mixture was stirred at 0° C. for 5 h and raised toroom temperature over night. 10 ml of HCl (10%) were added slowly andthe mixture was evaporated to near dryness under reduced pressure. Theresidue was suspended in saturated NaHCO₃ (50 ml) and extracted with3×50 ml diethyl ether, washed with brine and dried over MgSO₄.Purification by flash chromatography eluting with diethyl ether pentane5:95, gave 10.1 g (95%) of the title compound. R_(f) 0.66 (diethylether: pentane 20:80). ¹H NMR δ: 2.25 (s, 3H), 6.96 (d, J=10.2Hz, 1H),7.15 (d, J=10.2H, 1H), 7.05 (dd, J=7.6Hz, 2.6Hz, 1H), 7.24 (m, 3H), 7.34(m, 2H), 7.40 (m, 3H). ¹³C NMR δ: 21.4, 112.5, 117.3, 122.5, 122.8,123.7, 124.9, 128.4, 132.2, 133.6, 133.9, 143.6, 145.3, 186.6.

5-Methyl-3-phenyl-inden-1-one

To a suspension of anhydrous K₂CO₃ (9.76 g, 70.6 mmol) in dry DMF (100ml) was added 1-(2-bromo-4-methyl-phenyl)-3-phenyl-propenone (8.40 g,28.3 mmol), and the mixture was deaerated with dry argon for 15 min.Triphenylphosphine (0.73 g, 2.83 mmol) was added followed by PdCl₂ (0.20g, 1.13 mmol). The mixture was heated at 80° C. until NMR sampleindicated disappearance of starting material (5 h). The mixture wasreduced to half volume under reduced pressure and poured on ice:water(200 ml). Extractive work-up with CH₂Cl₂ followed by flashchromatography eluting with diethyl ether:pentane 5:95 gave 4.2 g (72%)of the title compound. R_(f) 0.62 (diethyl ether: pentane 20:80). IR(neat cm⁻¹): 1704, 1606, 1355, 1101, 815, 743. ¹H NMR δ: 2.40 (s, 3H),5.99 (s, 1H), 7.11 (d, J=7.2Hz, 1H), 7.18 (s, 1H), 7.43 (d, J=7.6Hz,1H), 7.53 (m, 3H), 7.66 (m, 2H). ¹³C NMR δ: 22.1, 122.7, 122.9, 123.5,127.4, 128.6, 128.9, 129.2, 129.9, 130.3, 133.2, 143.7, 144.4, 162.4. MS(EI 70 eV) m/z (rel. intensity): 220 (100) [M⁺], 205 (75), 191 (51), 177(10), 165 (15).

5-Methyl-3-phenyl-(S)-1H-inden-1-ol

(R)-MeCBS catalyst (0.22 ml, 1M, 0.22 mmol) was mixed in 5 ml of dryTHF, and stirred for 1 h at room temperature. After cooling to 0° C.,2.5 ml of 2M BH₃:Me₂S (4.99 mmol) in THF were added.5-Methyl-3-phenyl-inden-1-one (1.00 g, 4.54 mmol) was added as asolution in toulene (2 ml) over 2 h via a syringe pump. The reaction wasfollowed by TLC. After completeness, methanol (0.6 ml, 17 mmol) wasadded at 0° C. and the mixture was evaporated to dryness. Flashchromatography eluting with ethyl acetate:pentane 10:90 gave 0.96 g(95%) of the title compound. R_(f) 0.35 (ethyl acetate:pentane 20:80)(ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 24.53min. (R)-isomer 27.22 min. 93% ee. IR (neat cm⁻¹): 3300, 1605, 1446,949, 813. ¹H NMR δ: 1.40 (s, 1H), 2.40 (s, 3H), 5.27 (d, J=8Hz, 1H),6.43 (d J=2Hz, 1H), 7.18 (d, J=8Hz, 1H), 7.27 (s, 1H), 7.47 (m, 4H),7.59 (m, 2H). ¹³C NMR δ: 21.6, 76.2, 121.6, 123,6, 126.9, 127.6, 128.2,128.6, 134.1, 134.9, 138.2, 142.1, 143.7, 145.6. MS (EI 70eV) m/z (rel.intensity): 220 (100) [M⁺], 207 (71), 178 (66), 144 (42), 116 (23).

5-Methyl-3-(S)-phenyl-indan-1-one

5-Methyl-3-phenyl-(S)-1H-inden-1-ol (750 mg, 3.41 mmol) and DABCO (190mg, 1.71 mmol) were dissolved in dry THF:triethylamine 20:1 (15 ml) andrefluxed for 3 h. The reaction mixture was evaporated to dryness. Flashchromatography eluting with ethyl acetate:pentane 5:95 gave 690 mg (92%)of the title compound. R_(f) 0.62 (ethyl acetate:pentane 20:80)(ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 19.12min, (R)-isomer 22.33 min, 89% ee. IR (neat cm⁻¹): 3027, 2361, 1710,1605, 1280, 1238, 1040. ¹H NMR δ: 2.39 (s, 3H), 2.69 (dd, J=3.0, 19.2Hz,1H), 3.23 (dd, J=8.0, 19.2Hz, 1H), 4.53 (q, J=4Hz, 1H), 7.07 (s, 1H),7.14 (d, J=8.4Hz, 1H), 7.15 (s, 1H), 7.26 (m, 2H), 7.33 (m, 2H), 7.72(d, J=7.6Hz, 1H), ¹³C NMR δ: 22.1, 44.3, 46.9, 123.2, 126.9, 126.9,127.0, 127.6, 128.9, 134.5, 143.8, 146.3, 158.4, 205.5. MS (EI 70 eV)m/z (rel. intensity): 220 (100) [M⁺], 207 (55), 194 (19), 178 (60), 144(10).

6-Methyl-4-(S)-phenyl-chroman-2-one

5-Methyl-3-(S)-phenyl-indan-1-one (400 mg, 1.8 mmol) and mCPBA (98%, 485mg, 2.8 mmol) were suspended in dry CH₂Cl₂ (6 ml) at 0° C. followed byTsOH:H₂O (20 mg). The reaction was kept at 4° C. for 48 h. The mixturewas diluted with 10 ml of CH₂Cl₂ and washed with 2×10 ml of saturatedNa₂SO₃, saturated NaHCO₃ and brine. Flash chromatography eluting withethyl acetate:pentane 10:90 gave 390 mg (90%) of the title compound.R_(f) 0.83 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 mL/min ofhexane/isopropanol 95/5 (S)-isomer 15.18 min, (R)-isomer 17.42 min, 89%ee. IR (neat cm⁻¹): 2900, 2360, 1769, 1495, 1208, 1145. ¹H NMR δ: 2.28(s, 3H), 3.05 (m, 1H), 4.32 (t, J=6.8Hz, 1H), 6.98 (s, 1H), 7.04 (d,J=8.4Hz, 1H), 7.11 (dd, J=2.0, 8.4Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.19(s, 1H), 7.33 (m, 3H) ¹³C NMR δ: 20.7, 37.1, 40.7, 116.8, 125.3, 127.5,127.6, 128.6, 129.1, 129.3, 134.3, 140.5, 149.6, 167.8. MS (EI 70 eV)m/z (rel. intensity): 238 (55) [M⁺], 220 (57), 195 (100), 181(10), 165(12), 152 (9).

(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine(tolterodine)

Tolterodine may be prepared from 6-methyl-4-(S)-phenyl-chroman-2-one asobtained above by method steps corresponding to Examples 3 and 4 of theabove-mentioned U.S. Pat. No. 5,922,914 (the full disclosure of which isincorporated by reference herein), i.e. by (i) reducing the lactone6-methyl-4-(S)-phenyl-chroman-2-one with dissobutylaluminiumhydride intoluene solution at −20 to −25° C. to the corresponding hydroxycompound, 6-methyl-4-(S)-phenyl-chroman-2-ol; (ii) reductively aminatingthe 6-methyl-4-(S)-phenyl-chroman-2-ol in methanol by reaction withdiisopropylamine and hydrogenation with palladium on carbon at 45-50 psiand 48° C., and subsequent filtration (solka floc) to obtain the titlecompound (tolterodine) in substantially enantiomerically pure form.

What is claimed is:
 1. A compound of the formula

wherein R₁ is methyl or hydroxymethyl in 5-position or 4-position, R₂ and R₃ are hydrogen, and Hal is Br or I, or a salt thereof.
 2. The compound of claim 1, wherein R₁ is methyl.
 3. The compound of claim 2, wherein R₁ is in the 4-position.
 4. A compound of the formula

wherein R₁ is hydroxymethyl in 5-position or 4-position, R₂ and R₃ are hydrogen, and Hal is Br, I or F, or a salt thereof.
 5. The compound of claim 4, wherein R₁ is in the 4-position.
 6. The compound of claim 5, wherein Hal is Br.
 7. A salt of a compound of the formula

wherein R₁ is methyl or hydroxymethyl in 5-position or 4-position, R₂ and R₃ are hydrogen, and Hal is Br, I or F.
 8. A compound of the formula

wherein R₁ is methyl or hydroxymethyl in 5-position or 4-position, R₂ and R₃ are hydrogen, and Hal is Br. 